Design, Synthesis and Molecular Docking Studies of Some Novel Hydrazone Derivatives Based on Trimetazidine as Selective and Potent AChE Inhibitors

ABSTRACT Alzheimer's disease (AD) is a progressive neurodegenerative disease, and cholinergic dysfunction is considered one of the fundamental pathological factors of this disease. Guided by the clinically used acetylcholinesterase (AChE) inhibitor donepezil, we explored trimetazidine dihydrochloride as an accessible starting scaffold to generate donepezil‐like features and to develop new anti‐AD candidates. Accordingly, 20 novel hydrazone derivatives were designed and synthesized based on trimetazidine dihydrochloride, and their structures were confirmed by spectroscopic methods. The compounds were evaluated for in vitro inhibition of AChE and butyrylcholinesterase (BChE) using donepezil and tacrine as reference inhibitors, respectively. Several derivatives displayed pronounced AChE inhibition, whereas most compounds showed weak or negligible activity toward BChE, indicating a generally favorable AChE‐selective profile. Among the series, compounds 3p , 3q and 3r exhibited selective inhibitory activity against AChE comparable to donepezil, with IC 50 values of 0.030 ± 0.001 μM, 0.085 ± 0.003 μM and 0.034 ± 0.001 μM, respectively. To rationalize the observed activity trends, molecular docking studies were performed, suggesting that the most active ligands adopt donepezil‐like binding modes spanning the catalytic and peripheral anionic sites and are further stabilized by π–π/π–cation contacts and hydrogen‐bonding interactions within the active gorge. Overall, these findings identify trimetazidine‐derived hydrazide‐hydrazones as a promising chemotype for the development of selective AChE inhibitors and provide a basis for further optimization and advanced biological validation.